Racemic guaifenesin (also referred to as 3-(2-methoxyphenoxy)-1,2-propanediol) has been known for some time to be clinically effective as an antitussive. Guaifenesin is widely used in racemic form as an expectorant in cough remedy formulations. While there have been no published reports about the pharmacological properties of the individual enantiomers of guaifenesin, it has recently been speculated that perhaps one enantiomer may have greater physiological activity or fewer undesired side effects than the other enantiomer. However, any possible interest in using an enantiomerically enriched form of guaifenesin for medicinal purposes would be tempered by the relatively high cost of obtaining guaifenesin of high optical purity using known synthetic techniques. Several reports suggest that the 2R and 2S isomers of guaifenesin could be prepared using (2R)- or (2S)-glycerol-1,2-acetone [see Nelson et al., J. Org. Chem. 42, 1006-1012 (1977); U.S. Pat. No. 5,025,031 (Preparation 10); ES 544,545 (Chem Abstracts 107:23070 g)]. Such a synthesis, however, involves at least three steps from a readily accessible starting material. Another report [Wang et al., Tetrahedron Letters 34 (14), 2267-2270 (1993)] indicates that a substituted aryl allyl ether may be asymmetrically dihydroxylated to afford enantiomercially enriched guaifenesin. However, the optical purity of the product obtained, as measured by e.e. value, is only 63%. The development of lower cost processes for obtaining highly enantiomerically enriched guaifenesin thus would be highly desirable.
The reaction of racemic glycidol with various phenols to yield aryl-.beta.,.gamma.-dihydroxypropyl ethers is disclosed in British Pat. No. 628,497. According to the publication, the reaction may be catalyzed by either tertiary amines or quaternary ammonium salts. However, as later noted in U.S. Pat. No. 4,390,732, the disadvantage of this reaction is that the yields are not very high. Additionally, according to the patent, if this general reaction is attempted with o-methoxyphenol for the purpose of preparing racemic guaifenesin, the product obtained is colored and has a very low purity. U.S. Pat. No. 4,390,732 instead recommends the use of a catalyst selected from various alkali metal-containing species in a solventless procedure.
We have now unexpectedly discovered that optically active guaifenesin of exceptionally high enantiomeric purity may be produced in excellent yield using enantiomerically enriched glycidol as a reactant and a tertiary amine as catalyst. This result was surprising in view of the warning in U.S. Pat. No. 4,390,732 that the reaction of racemic glycidol and o-methoxyphenol will yield unacceptable results.